The symptoms experienced by patients with neurodegenerative disorders like Parkinson's disease, Alzheimer's disease and other less common conditions are quite distinct. The basis for the characteristic clinical manifestations of each of the disorders is dysfunction and death of different neuronal cell populations. However, despite many important molecular genetic, pathological and biochemical advances in our understanding of neurodegenerative diseases, the basis for neuronal cell type-specificity remains a fundamental mystery. We will take a genetic approach to the problem of specific degeneration of subsets of postmitotic neurons. Our approach will be to perform unbiased forward genetic screens in Drosophila to outline pathways responsible for cell type-specific neurodegeneration in differentiated adult neurons. We will outline pathways that maintain viability of subsets of neurons both in otherwise normal neurons and in neurons expressing toxic proteins implicated in Alzheimer's and Parkinson's disease. Importantly, we have previously demonstrated relevant neuronal cell type-specific degeneration in our Parkinson's and Alzheimer's disease models. Human homologs of candidates developed in the Drosophila system will then be examined for anatomic localization to vulnerable neurons in human tissue. In the longer term, the cell type-specific pathways of neuronal vulnerability identified in the current proposal will provide attractive therapeutic targets in Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: As doctors and family members alike know, patients with Alzheimer's disease often experience loss of memory and other cognitive problems while Parkinson's disease is usually manifest by tremor, slowness of movement and rigidity. Although we know that these characteristic disease symptoms reflect loss of specific neurons in the brains of these patients, we have very little insight into why specific subsets of neurons are lost in particular diseases. Our studies seek to determine the mechanisms that underlie specific loss of identified neurons as part of a longer term effort to devise effective treatments for these devastating disorders.